Human immunodeficiency viruses (HIVs) are a group of human retroviruses with varying abilities to cause pathogenesis of the acquired immunodeficiency syndrome (AIDS). Gene therapy holds great promise as a therapeutic modality for human diseases, including cancer and AIDS. One objective of this project is to develop human retroviral vectors for gene transfer. HIV, especially HIV-2 as a vector, has the distinct advantage of cell tropism for targeted gene delivery and the ability to transduce non-dividing cells, including stem cells. To address the issue of parameters governing expression and packaging, a series of HIV-2-based vectors have been constructed containing long terminal repeats (LTR) for regulated and high level expression: gag sequences for packaging efficiency, neo gene for marker selection, and those containing split genome to minimize helper virus production. Efforts are underway to identify a unique combination of expression vectors and packaging cell lines for efficient gene transfer in human cells. The two HIV virus groups, HIV-1 and HIV-2, differ from each other in many aspects of their natural history and pathogenic potential. Recently, we identified a remarkable difference between the two virus types: that is, HIV-2 can downmodulate HIV-1 without the reciprocal effect of HIV-1 on HIV-2. This is consistent with the notion that HIV-2 may provide protection against HIV-1 infection in populations at risk. This observation also provides added incentive to develop HIV-2 based vectors for gene therapy. Human CD8+ cells have been known to produce HIV suppressive factors whose identity remained unknown until we published our report identifying members of beta chemokines family as the suppressive factors. These observation also helped solve another mystery of HIV: namely, the co-receptors used by HIV for infection of specific target cells. Since chemokines have both chemotaxis and antiviral activities, we are now mapping the functional domain to achieve specificity.